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BACKGROUND: While chimeric antigen receptor (CAR) T-cell therapy has revolutionized the treatment outcomes of relapsed/refractory hematological malignancies, this therapy is associated with post-treatment cytopenias, which can pose a challenge to its safe administration. This study describes the management of post-CAR T cytopenias using the thrombopoietin mimetic eltrombopag. METHODS: This retrospective analysis included adult patients with lymphoma or myeloma who received CAR T-cell therapy at two academic medical centers. Eltrombopag was initiated for patients who had persistent high-grade leukopenia and/or thrombocytopenia beyond 21 days post-CAR T infusion. Risk factors and outcomes were assessed and compared for patients who did or did not receive eltrombopag. RESULTS: Among the 185 patients analyzed, a majority (88%) experienced thrombocytopenia or leukopenia at day +30 post-CAR T infusion. A total of 42 patients met the criteria for eltrombopag treatment and initiated therapy. Patients who received eltrombopag were more likely to have pre-existing cytopenias at lymphodepletion, receive bridging therapy, experience an infection, or require intensive care. Recovery from cytopenias occurred within 180 days for a majority (94%) of patients. CONCLUSIONS: The use of eltrombopag for post-CAR T leukopenia and thrombocytopenia was considered safe without any significant toxicities. The use of eltrombopag for post-CAR T cytopenias might be effective in a high-risk patient population but requires further study.
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Anemia , Benzoatos , Citopenia , Neoplasias Hematológicas , Hidrazinas , Leucopenia , Pirazóis , Receptores de Antígenos Quiméricos , Trombocitopenia , Adulto , Humanos , Estudos Retrospectivos , Recidiva Local de Neoplasia , Trombocitopenia/tratamento farmacológico , Trombocitopenia/etiologia , Imunoterapia Adotiva/efeitos adversos , Anemia/etiologia , Neoplasias Hematológicas/complicações , Neoplasias Hematológicas/terapiaRESUMO
High-dose chemotherapy followed by autologous hematopoietic stem cell transplantation is the standard of care for eligible patients with newly diagnosed multiple myeloma leading to prolonged progression free and overall survival. Successful engraftment following hematopoietic stem cell infusion requires adequate stem cell doses. Current mobilization regimens include granulocyte colony-stimulating factor (G-CSF) with or without plerixafor. Motixafortide is a recently approved agent that can be used in combination with G-CSF for mobilization. In the absence of any head-to-head trials comparing the two products, this article aims to outline the similarities and differences of these two agents. Though moxitafortide has a more favorable pharmacokinetic profile in comparison to plerixafor, in clinical trials, the agents demonstrated similar efficacy. In addition, the use of motixafortide in clinical practice may be limited by product cost as well as administration and monitoring requirements.
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BACKGROUND: Cytokine release syndrome (CRS) and immune effector cell-associated neurologic syndrome (ICANS) are well-documented toxicities of CAR T-cell therapy. To mitigate excessive toxicity, our center has formulated treatment protocols (early vs. standard) for timely management of CRS and ICANS with tocilizumab and/or corticosteroids. METHODS: This retrospective, single-center analysis included patients treated with CAR T-cell therapy. The goal was to describe the association of two management protocols with toxicity and efficacy outcomes. RESULTS: Fifty-five percent of the 40 patients assigned to early management, out of which 5% and 9% developed grade 3+ CRS and ICANS, respectively. Seventy-seven percent and 41% of these patients received tocilizumab and corticosteroids, respectively. Forty-five percent of patients were stratified as standard management, out of which 0% and 11% developed grade 3+ CRS and ICANS, respectively. Seventeen percent and 28% of these patients received tocilizumab and corticosteroids, respectively. The day +90 overall response rate (ORR) for all patients was 63%, with an ORR of 89% for those managed per early management versus 50% for those managed per standard protocol. CONCLUSION: Early use of tocilizumab and corticosteroids is effective in preventing excessive CAR-T-related toxicities with no negative impact on efficacy.
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Corticosteroides , Imunoterapia Adotiva , Humanos , Imunoterapia Adotiva/efeitos adversos , Estudos Retrospectivos , Síndrome , Corticosteroides/uso terapêuticoRESUMO
INTRODUCTION: Cytokine release syndrome (CRS) and immune effector cell-associated neurotoxicity syndrome (ICANS) are common toxicities associated with chimeric antigen receptor (CAR) T-cell therapy. Severe grade 3 or higher ICANS is less common and requires the use of corticosteroids with or without an Interleukin (IL)-6 receptor antagonist. Although corticosteroids are effective in the management of CRS and ICANS, their impact on CAR T efficacy remains unknown. CASE REPORT: We present the case of a 65-year-old male who received CAR T-cell therapy with brexucabtagene autoleucel for stage I/II Mantle Cell Lymphoma (MCL) and achieved complete remission despite receiving a prolonged course of corticosteroids for severe ICANS. MANAGEMENT AND OUTCOME: The patient received treatment with high-dose corticosteroids, tocilizumab, and anakinra, in addition to multiple antiepileptic agents. Despite a remitting relapsing pattern of ICANS, the patient not only recovered from the life-threatening complication but also achieved a complete remission at three months post CAR T. CONCLUSION: This case describes the successful use of corticosteroids for the management of ICANS in a patient treated with CAR T-cell therapy for MCL.
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Linfoma de Célula do Manto , Síndromes Neurotóxicas , Receptores de Antígenos Quiméricos , Masculino , Humanos , Adulto , Idoso , Imunoterapia Adotiva , Receptores de Antígenos Quiméricos/uso terapêutico , Pacientes , Corticosteroides/uso terapêuticoRESUMO
BCMA-directed chimeric antigen receptor T-cell (CAR T) therapies, including idecabtagene vicleucel (ide-cel) and ciltacabtagene autoleucel (cilta-cel), have transformed the treatment landscape for relapsed-refractory multiple myeloma (RRMM), offering remarkable efficacy with hallmark toxicity risks of cytokine release syndrome (CRS) and immune effector cell-associated neurotoxicity syndrome (ICANS). The FDA mandates a 4-week monitoring period at the treatment center as part of a Risk Evaluation and Mitigation Strategy (REMS) to monitor and manage these toxicities, which, while prudent, may add unnecessary challenges related to access and socioeconomic disparities. We sought to assess CRS and ICANS onset and duration, as well as causes of non-relapse mortality (NRM) in real-world BCMA CAR T recipients in order to better inform future changes to the monitoring guidelines for CAR T recipients. This is a retrospective study across four academic centers that examined 129 ide-cel and cilta-cel recipients that received CAR T cell infusions from May 2021 to June 2023. Infusion and toxicities were managed per institutional guidelines in accordance with previously published guidelines. While differences were noted in the incidence and duration of CRS/ ICANS between ide-cel and cilta-cel, late-onset CRS and ICANS were rare after 2 weeks following infusion (0% and 1.6%, respectively). NRM was driven by hemophagocytic lymphohistiocytosis and infections in the early follow-up period (1.1% until Day 29), then by infections through three months post-infusion (1.2%). Our findings suggest that 25% of patients had to relocate for 4 weeks due to distance from the treatment center. With the low risk of CRS and ICANS after 2 weeks, a flexible shorter monitoring period may be reasonable, emphasizing collaboration with referring oncologists to improve NRM.
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Síndrome da Liberação de Citocina , Imunoterapia Adotiva , Mieloma Múltiplo , Humanos , Mieloma Múltiplo/mortalidade , Mieloma Múltiplo/terapia , Imunoterapia Adotiva/efeitos adversos , Feminino , Pessoa de Meia-Idade , Masculino , Idoso , Síndrome da Liberação de Citocina/etiologia , Síndrome da Liberação de Citocina/mortalidade , Estudos Retrospectivos , Antígeno de Maturação de Linfócitos B/imunologia , Adulto , Receptores de Antígenos Quiméricos/uso terapêutico , Receptores de Antígenos Quiméricos/imunologia , Síndromes Neurotóxicas/etiologia , Síndromes Neurotóxicas/mortalidade , Fatores de TempoRESUMO
For patients with newly diagnosed multiple myeloma (MM) undergoing high-dose chemotherapy and autologous stem cell transplantation (HDT-ASCT), hematopoietic stem cell mobilization can be affected by induction chemotherapy. In clinical trials, the addition of daratumumab (dara) to a triplet backbone lowered hematopoietic stem cell yield, necessitating the administration of plerixafor to achieve the desired yield for ASCT. Here we describe our experience of stem cell mobilization and collection after dara-based and non-dara-based induction regimens. This single-center retrospective analysis included patients with newly diagnosed MM who had received induction chemotherapy and were candidates for upfront HDT-ASCT. Based on the induction regimen used, patients were divided into 2 groups, RVd (lenalidomide, bortezomib, and dexamethasone) and DRVd (RVd with the addition of dara). Based on our institutional practice, patients received pegylated growth colony-stimulating factor (G-CSF) on day -3 (at 0900 hours) in combination with plerixafor on day -1 (at 2300 hours) as a preemptive mobilization strategy. Patients continued apheresis for 1 to 3 days until the goal dose of hematopoietic stem cells was collected (2.5 × 106 cells/kg for one ASCT and 5.0 × 106 cells/kg for 2 ASCTs). Patients with a suboptimal stem cell yield on day 1 received additional doses of plerixafor with or without G-CSF. A total of 101 patients with newly diagnosed MM who underwent mobilization between July 2021 and June 2022 were analyzed. The median patient age was 61 years (range, 36 to 80 years), and 51.5% of the cohort was female. Patients received a median of 5 (range, 2 to 12) cycles of induction chemotherapy, with a median of 4 (range, 2 to 12) cycles of DRVd and 6 (range, 3 to 12) cycles of RVd. The median number of CD34+ cells collected in the DRVd and the RVd groups was 6.54 × 106/kg and 6.78 × 106/kg, respectively. Target CD34+ stem cells were collected in a median of 1 day (range, 1 to 4 day) in each group. On average, more patients in the DRVd group compared to the RVd group received additional doses of plerixafor (51% versus 43%) and additional doses of GCSF (19% versus 14%) to achieve the target stem cell yield. There were no mobilization failures or grade 3+ mobilization-related adverse events reported in either group. The addition of daratumumab to the RVd induction regimen did not lead to any clinically significant differences in stem cell yield or number of collection days, provided that the patient received preemptive G-CSF and plerixafor. Patients with suboptimal collection on day 1 were able to collect adequate stem cells with additional doses of plerixafor with or without G-CSF.
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Transplante de Células-Tronco Hematopoéticas , Compostos Heterocíclicos , Mieloma Múltiplo , Humanos , Feminino , Adulto , Pessoa de Meia-Idade , Idoso , Idoso de 80 Anos ou mais , Mobilização de Células-Tronco Hematopoéticas , Mieloma Múltiplo/tratamento farmacológico , Estudos Retrospectivos , Quimioterapia de Indução , Transplante Autólogo , Compostos Heterocíclicos/uso terapêutico , Compostos Heterocíclicos/efeitos adversos , Fator Estimulador de Colônias de Granulócitos/efeitos adversosRESUMO
BACKGROUND: The diversity in the genomic landscape of advanced and metastatic tumors calls for combination therapies based on the genomic signature associated with each tumor. Determining safe and tolerable doses for novel combinations of oncology drugs is essential for a precision medicine approach, but can also require dose reductions. Trametinib, palbociclib, and everolimus are among the targeted therapies most often used in novel combinations at our precision medicine clinic. OBJECTIVE: To evaluate the safe, tolerable dosing of trametinib, palbociclib, and everolimus when used as part of novel combinations with other agents for the treatment of advanced or metastatic solid tumors. METHODS: This retrospective study included adult patients with advanced or metastatic solid tumors who received trametinib, everolimus, or palbociclib plus other therapies as a part of novel combinations between December 2011 and July 2018 at the University of California San Diego. Patients were excluded if they received trametinib, everolimus, or palbociclib in standard combinations, such as dabrafenib plus trametinib, everolimus plus fulvestrant, everolimus plus letrozole, and palbociclib plus letrozole. Dosing and adverse events were determined through a review of the electronic medical records. A safe, tolerable drug combination dose was defined as being tolerated for at least 1 month, with no clinically significant serious adverse events. RESULTS: A safe, tolerable dose was determined for 76% of the 71 patients who received trametinib, 88% of the 48 patients who received everolimus, and 73% of the 41 patients receiving palbociclib when used in combination with other therapies. For patients with clinically significant adverse events, dose reductions were attempted in 30% of the trametinib recipients, in 17% of everolimus recipients, and in 45% of palbociclib recipients. When used in combination with other therapies, the optimal dosing of trametinib, palbociclib, and everolimus was lower than the standard single-agent dosing: it was 1 mg daily for trametinib; 5 mg daily for everolimus; and 75 mg daily, for 3 weeks on and 1 week off for palbociclib. Of note, everolimus could not be given concomitantly with trametinib at these doses. CONCLUSION: Safe and tolerable dosing of novel combination therapies that includes trametinib, everolimus, or palbociclib is feasible for a precision medicine approach. However, neither results from this study nor results from previous studies could support the use of everolimus in combination with trametinib, even at reduced doses.
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BACKGROUND: Fever is a hallmark symptom of cytokine release syndrome (CRS) after chimeric antigen receptor (CAR) T-cell therapy. Fever characteristics and the impact of fever on safety and efficacy post CAR T are not well understood. We sought to explore the impact of fever and its characteristics on safety and efficacy post CAR T-cell therapy. PATIENTS AND METHODS: We reviewed 40 patients with various hematologic malignancies (non-Hodgkin lymphoma, acute lymphoblastic leukemia, multiple myeloma) treated with CAR T-cell therapy between March 2019 and March 2022. We evaluated all patients who developed fever after CAR T infusion and analyzed the association of fever with toxicity (CRS and neurotoxicity) and efficacy (overall response (ORR) and complete response (CR) at day +90 post CAR T infusion). Fever was defined as per Lee criteria (equal to or greater than 38°C). CRS and immune-effector cell associated neurotoxicity syndrome (ICANS) were graded using American Society for Transplantation and Cellular Therapy grading system. RESULTS: Fever occurred in 75% (30/40) of patients. Rates of all grade and grade 3+ CRS and ICANS were 75%, 2%, 33% and 10%, respectively. Fever occurred within 24 and 72 hours after CAR T infusion in 40% and 53% of patients, respectively. Fifty percent of patients received tocilizumab (toci) for CRS. After the first dose of toci, fever recurred in 38% of the patients, of which 67% had recurrence within 24 hours. Day +90 CR rates were 43% and 10% in patients with and without fever, respectively (Table 3). CONCLUSION: While fever is common after CAR T-cell therapy, early-onset and higher magnitude do not appear to affect safety or efficacy of CAR T. Absence of fever may affect response to CAR T.
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Leucemia-Linfoma Linfoblástico de Células Precursoras , Receptores de Antígenos Quiméricos , Humanos , Imunoterapia Adotiva/efeitos adversos , Síndrome da Liberação de Citocina/terapia , Síndrome da Liberação de Citocina/tratamento farmacológico , Leucemia-Linfoma Linfoblástico de Células Precursoras/tratamento farmacológico , Febre/etiologia , Terapia Baseada em Transplante de Células e Tecidos , Receptores de Antígenos de Linfócitos T/genéticaRESUMO
OBJECTIVE: To compare classic Ayurveda, methotrexate (MTX), and their combination in a double-blind, randomized, double-dummy, pilot trial in rheumatoid arthritis (RA) for 36 weeks. METHODS: Forty-three seropositive RA patients by American College of Rheumatology (ACR) criteria with disease duration of less than 7 years were assigned to the following treatment groups: MTX plus Ayurvedic placebo (n = 14), Ayurveda plus MTX placebo (n = 12), or Ayurveda plus MTX (n = 17). Outcomes included the Disease Activity Score (DAS28-CRP), ACR20/50/70, and Health Assessment Questionnaire--Disability Index. All measures were obtained every 12 weeks for 36 weeks. Analyses included descriptive statistics, analysis of variance, χ², or Student t test. The unique features of this study included the development of placebos for each Ayurvedic pharmacological dosage form and individualization of Ayurvedic therapy. RESULTS: All groups were comparable at baseline in demographics and disease characteristics. There were no statistically significant differences among the 3 groups on the efficacy measures. ACR20 results were MTX 86%, Ayurveda 100%, and combination 82%, and DAS28-CRP response were MTX -2.4, Ayurveda -1.7, and combination -2.4. Differences in adverse events among groups were also not statistically significant, although the MTX groups experienced more adverse event (MTX 174, Ayurveda 112, combination 176). No deaths occurred. CONCLUSIONS: In this first-ever, double-blind, randomized, placebo-controlled pilot study comparing Ayurveda, MTX, and their combination, all 3 treatments were approximately equivalent in efficacy, within the limits of a pilot study. Adverse events were numerically fewer in the Ayurveda-only group. This study demonstrates that double-blind, placebo-controlled, randomized studies are possible when testing individualized classic Ayurvedic versus allopathic treatment in ways acceptable to western standards and to Ayurvedic physicians. It also justifies the need for larger studies.
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Antirreumáticos/uso terapêutico , Artrite Reumatoide/terapia , Ayurveda , Metotrexato/uso terapêutico , Adulto , Relação Dose-Resposta a Droga , Método Duplo-Cego , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Avaliação de Resultados em Cuidados de Saúde , Projetos Piloto , Índice de Gravidade de Doença , Resultado do TratamentoRESUMO
An abuse-deterrent, microsphere-in-capsule extended-release formulation of oxycodone myristate (Xtampza® ER, Collegium Pharmaceutical Inc, Canton, Massachusetts), was approved by the FDA in 2016 for the management of pain. The advantage of this formulation of oxycodone is that the microspheres can be administered via enteral tubes without compromising the long-acting formulation. This case series characterizes the experiences of five head and neck cancer patients initiated on oxycodone myristate through enteral tube administration for control of cancer-related pain. The primary outcome of patient reported subjective improvement in pain within one week occurred in all five patients. The median time to pain control was 4 days. The safety profile of oxycodone myristate was consistent with the package insert with no new findings reported. Oxycodone myristate can be an appropriate long-acting opioid analgesic option for patients requiring enteral tube administration of medications to achieve adequate cancer-related pain control.
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Neoplasias de Cabeça e Pescoço , Transtornos Relacionados ao Uso de Opioides , Analgésicos Opioides , Preparações de Ação Retardada/uso terapêutico , Neoplasias de Cabeça e Pescoço/complicações , Neoplasias de Cabeça e Pescoço/tratamento farmacológico , Humanos , Transtornos Relacionados ao Uso de Opioides/tratamento farmacológico , Oxicodona , Dor/tratamento farmacológico , Dor/etiologiaRESUMO
INTRODUCTION: Patients with central nervous system malignancies have limited representation in studies evaluating DOACs for VTE treatment. This study evaluated the safety and efficacy of DOACs in comparison with LMWH for cancer-associated VTE in patients with primary brain tumors or secondary brain metastases. MATERIALS & METHODS: In this multicenter, retrospective cohort study, adult patients with a diagnosis of primary brain tumor or secondary brain metastases who received either a DOAC or LMWH for treatment of cancer-associated VTE were evaluated. The primary outcome was the cumulative incidence of any intracranial hemorrhage within a 6-month period following the initiation of anticoagulation. Secondary outcomes included the cumulative incidence of any bleeding event, and recurrent VTE events. RESULTS: Between January 1, 2012 and October 9, 2019, one-hundred eleven patients met inclusion criteria. The 6-month cumulative incidence of intracranial hemorrhage was 4.3% (95% CI, 0.74-13.2%) in the DOAC group, compared to 5.9% (95% CI, 1.5-14.9%) in the LMWH group (p = 0.61). The 6-month cumulative incidence of bleeding events was 14.3% (95% CI, 6.2-25.8%) in the DOAC group, compared to 27.8% (95% CI, 15.5-41.6%) in the LMWH group (p = 0.10). The 6-month cumulative incidence of recurrent VTE events was 5.6% in the DOAC group (95% CI, 1.5-14.2%), compared to 6.6% in the LMWH group (95% CI, 1.7-16.5%) (p = 0.96). No differences were found with respect to other secondary outcomes. CONCLUSION: There were no significant differences in bleeding or recurrent VTE events between DOACs and LMWH. These findings suggest DOACs may be safe and effective for VTE treatment in this patient population.
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Neoplasias Encefálicas , Tromboembolia Venosa , Anticoagulantes/efeitos adversos , Neoplasias Encefálicas/complicações , Heparina de Baixo Peso Molecular/efeitos adversos , Humanos , Estudos Retrospectivos , Tromboembolia Venosa/tratamento farmacológicoAssuntos
Antígeno de Maturação de Linfócitos B , Mieloma Múltiplo , Humanos , Mieloma Múltiplo/tratamento farmacológico , Mieloma Múltiplo/imunologia , Antígeno de Maturação de Linfócitos B/imunologia , Antineoplásicos/efeitos adversos , Antineoplásicos/administração & dosagem , Antineoplásicos/farmacologia , Doenças Hematológicas/imunologia , Fatores de Tempo , Anticorpos Monoclonais/administração & dosagem , Anticorpos Monoclonais/farmacologia , Anticorpos Monoclonais/efeitos adversosAssuntos
Neoplasias Hematológicas , Receptores de Antígenos Quiméricos , Humanos , Receptores de Antígenos Quiméricos/genética , Imunoterapia Adotiva/efeitos adversos , Neoplasias Hematológicas/terapia , Terapia Baseada em Transplante de Células e Tecidos , Receptores de Antígenos de Linfócitos T/genéticaRESUMO
Seafloor sediment flows (turbidity currents) are among the volumetrically most important yet least documented sediment transport processes on Earth. A scarcity of direct observations means that basic characteristics, such as whether flows are entirely dilute or driven by a dense basal layer, remain equivocal. Here we present the most detailed direct observations yet from oceanic turbidity currents. These powerful events in Monterey Canyon have frontal speeds of up to 7.2 m s-1, and carry heavy (800 kg) objects at speeds of ≥4 m s-1. We infer they consist of fast and dense near-bed layers, caused by remobilization of the seafloor, overlain by dilute clouds that outrun the dense layer. Seabed remobilization probably results from disturbance and liquefaction of loose-packed canyon-floor sand. Surprisingly, not all flows correlate with major perturbations such as storms, floods or earthquakes. We therefore provide a new view of sediment transport through submarine canyons into the deep-sea.